Choroidal Neovascularization Associated With Focal Choroidal Excavation JAE HYUNG LEE AND WON KI LEE
PURPOSE:
To describe the clinical and imaging characteristics of choroidal neovascularization (CNV) accompanied by focal choroidal excavation. DESIGN: Retrospective, interventional case series. METHODS: The medical records of 16 patients (16 eyes) were reviewed. Imaging findings including fluorescein angiography (FA), indocyanine green angiography, and spectral-domain optical coherence tomography (SD OCT) were analyzed. RESULTS: CNV complexes were primarily located beneath the retinal pigment epithelium (type 1 CNV) in 9 eyes and in the subneurosensory retinal space (type 2 CNV) in 7 eyes, as assessed by SD OCT. Seven of 8 patients over 50 years old had type 1 CNV, and 6 of 8 patients under 50 had type 2 lesions. All 7 eyes with type 2 CNV exhibited classic CNV on FA. Additionally, 7 of 9 eyes with type 1 CNV had the classic pattern, and in these eyes, the CNV complexes were confined to the concavity of choroidal excavation. In 15 patients treated by anti–vascular endothelial growth factor (anti-VEGF) injections, the mean best-corrected visual acuity improved from 20/44 to 20/26 with a mean of 3.7 injections during a mean follow-up period of 14.5 months. CONCLUSIONS: The CNV growth pattern and extent seem to be determined by the degree of damage to the retinal pigment epithelium/Bruch membrane complex resulting from choroidal excavation, as well as age. Neovascular complexes tend to be located within the boundary of choroidal excavation and are revealed as classic patterns on FA, even in type 1 CNV. AntiVEGF was notably effective for treating these lesions, with a low rate of recurrence. (Am J Ophthalmol 2014;157:710–718. Ó 2014 by Elsevier Inc. All rights reserved.)
C
HOROIDAL EXCAVATION WAS FIRST REPORTED
as an unusual finding on time-domain optical coherence tomography (OCT) by Jampol and
Accepted for publication Dec 4, 2013. From the Department of Ophthalmology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Inquiries to Won Ki Lee, Department of Ophthalmology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-701, South Korea; e-mail: [email protected]
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associates.1 After a few reports of similar cases detected by spectral-domain optical coherence tomography (SD OCT),2,3 Margolis and associates4 named this entity focal choroidal excavation. In 2 recent reports, most focal choroidal excavation lesions were shown to remain stable over a 1- or 3-year follow-up period.4,5 In a portion of patients, there was a history of central serous chorioretinopathy (CSC) or the concomitant presence of CSC. Cicatrized subretinal neovascularization was also noted at initial presentation in certain patients, while in others, secondary choroidal neovascularization (CNV) developed during the follow-up. The authors suggested a possible association between abnormal choroidal circulation in focal choroidal excavation and pathologic lesions. However, it has not been determined whether CNV develops as a clinical consequence of focal choroidal excavation or if they are 2 unrelated diseases that were coincidentally detected simultaneously. The paucity of cases has made it difficult to make conclusions regarding the role of focal choroidal excavation in CNV development. There are several characteristic features of focal choroidal excavation that indicate that it may provide the appropriate milieu for CNV development. Previous studies showed that focal choroidal thinning and hypoperfusion was associated with focal choroidal excavation. Additionally, varying degrees of pigmentary disturbances and retinal pigment epithelium (RPE) alterations were noted.3–5 It is also possible that the stretching of the RPE/ Bruch membrane in the area of choroidal excavation can result in a focal break in the Bruch membrane, which induces neovascular proliferation from the choroid, as in Gass type 2 CNV. Gass classified the patterns of choroidal neovascular growth into the 2 following pathologic types: type 1, the growth of new vessels beneath the RPE; and type 2, the growth of new vessels in the subsensory retinal space.6 Elderly patients with age-related macular degeneration (AMD), which is associated with diffuse loosening of the firm attachment of the RPE to the Bruch membrane, are prone to developing type 1 CNV. This form of neovascularization is less permeable and proliferates slowly.7,8 Fluorescein angiography (FA) reveals a pattern that is ‘‘poorly defined’’ with minimal leakage, which is also described as occult CNV. In contrast, type 2 CNV occurs primarily in patients younger than 50 years and is associated with focally destructive lesions affecting the
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RPE/Bruch membrane. The firm attachment between the surrounding RPE and Bruch membrane in young individuals was postulated to explain the type 2 growth pattern. Type 2 CNV tends to proliferate rapidly, and FA typically exhibits a ‘‘well-defined’’ pattern with intense leakage, also referred to as classic CNV.7,8 SD OCT enables us to observe the details of retinal structures and the level of retinal involvement in CNV. Studies using SD OCT demonstrated a relatively good correlation between the angiographic classification (occult vs classic) and the anatomic classification of CNV (type 1 vs type 2).9,10 The purpose of this study was to evaluate the detailed clinical and imaging characteristics in patients with CNV accompanied by focal choroidal excavation, focusing particularly on the association between the angiographic pattern and the anatomic pattern on OCT. We also suggest a hypothetical angiogenic process in this newly described disease entity.
METHODS WE ANALYZED THE MEDICAL RECORDS AND IMAGING
studies of 689 eyes from 653 consecutive patients with CNV or polypoidal choroidal vasculopathy who were referred to the ophthalmology department of Seoul St. Mary’s Hospital, The Catholic University of Korea, between the beginning of January 2009 and the end of March 2013. Sixteen patients were diagnosed as having CNV accompanied by focal choroidal excavation. Detailed clinical and imaging characteristics were evaluated in these patients. This retrospective study was approved by the Institutional Review Board of the Catholic Medical Center and conducted in accordance with the tenets of the Declaration of Helsinki. All patients received a complete ocular examination, including best-corrected visual acuity (BCVA) measurement using a Snellen visual acuity chart, slit-lamp biomicroscopy with a noncontact or contact lens, and OCT at baseline and at each follow-up visit. Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) was used for SD OCT examinations after November 2011. The raster scan of Spectralis OCT was performed on each eye centered at the fovea using 2 scan protocols: a conventional protocol and an enhanced depth imaging (EDI) protocol.11 Before that time, Cirrus OCT (Carl Zeiss Meditec, Dublin, California, USA) with macular cube program consisting of 128 horizontal lines of 512 A-scans was used. All 16 patients underwent EDI OCT using Spectralis OCT at least once during their follow-up. FA and indocyanine green angiography (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany) were performed at baseline and on a patient-by-patient basis thereafter. However, indocyanine green angiography (ICGA) was not VOL. 157, NO. 3
performed in 4 eyes at baseline. The Topcon IMAGEnet Digital Imaging System (Topcon, Tokyo, Japan) was used for FA examination in some patients. The diagnosis of focal choroidal excavation was based on SD OCT findings of local excavation of the RPE and Bruch membrane line. Staphylomatous excavation of the sclerochoroidal junction was ruled out with EDI OCT. EDI OCT was used to determine choroidal thickness at the base of the focal choroidal excavation and the unaffected sites near the excavation by measuring the distance from the outer portion of the hyperreflective RPE line to the inner surface of the sclera with the digital calipers included in the review software. The ratio of the choroidal thicknesses of the 2 sites was calculated. The diagnosis and classification of CNV were based on the FA and SD OCT findings. According to FA, CNVs were labeled classic or occult based on the Treatment of AgeRelated Macular Degeneration With Photodynamic Therapy (TAP) protocol.12 The anatomic classification of CNV was made based on the location of the CNV membrane appearing as a highly reflective lesion on SD OCT with respect to the RPE band. CNV was classified as type 1 when the highly reflective lesion was primarily identified in the sub-RPE space and as type 2 when it was predominantly localized in the subretinal space. The topographic association between choroidal excavation and the hyperreflective lesion was also evaluated. The ICGA images were analyzed to identify aberrant vessels or polypoidal lesions and any abnormal hypofluorescent or hyperfluoresecnt areas. All patients were treated with intravitreal anti–vascular endothelial growth factor (anti-VEGF) injection with either bevacizumab (Avastin; Genentech, Inc, San Francisco, California, USA) or ranibizumab (Lucentis; Genentech Inc), except for 1 patient who was lost to follow-up. Anti-VEGF treatment was performed on an as-needed basis, after either an initial 2 or 3 consecutive injections or a single injection. Repeated injections were given whenever either intraretinal or subretinal fluid involving the fovea was detected on follow-up OCT. The patients were followed up regularly at 1- to 6-month intervals, depending on lesion activity, but the intervals did not exceed 3 months in patients over 50 years old.
RESULTS THE PATIENT CHARACTERISTICS ARE SUMMARIZED IN THE
Table. We studied 16 eyes in 16 Korean patients, 9 of whom were women. The mean age was 49.6 years (range, 28-86 years). Eight patients were under 50 years old; 2 among them had a history of CSC in the affected eyes and 1 patient had high myopia. Soft drusen was only noted in 1 of 8 patients over 50. None of the patients had a history of medical illness, medication use, or a family history of retinal disease. None of the cases were bilaterally affected,
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TABLE. Clinical Characteristics of Patients With Choroidal Neovascularization Associated With Focal Choroidal Excavation OCT
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Case No.
Age/Sex
1
39/M
Left
2
71/M
Left
3 4
86/F 28/M
Left Right
5
69/F
Left
6
45/M
Right
2.125 Subsensory
7
47/F
Left
6.5
Subsensory
8
55/M
Right
0.5
Sub-RPE
9
40/F
Right
2.75
Sub RPE
10
53/F
Right
3.125 Subsensory
11
29/F
Right
7.125 Subsensory
12
53/M
Left
0.5
13 14
66/M 54/F
Right Right
15
28/F
Left
16
30/F
Right
Eye
SE
12.5
CNV Pattern
Extent of CNV
FA CNV Pattern
ICGA
BCVA
Ratio of Choroidal F/U Focal Late Thicknessa (Months) Hypofluoresence Hyperfluoresence
Anti-VEGF (Nb)
Additional Injectionc
Initial
Final
20/25
Classic
NA
NA
0.50 (114/228)
19
Bevacizumab (1)
20/32
Within the Classic concavity 0.625 Sub-RPE Over the margin Occult 4.5 Subsensory Over the margin Classic
þ
þ
0.25 (54/216)
35
Ranibizumab (7)
þ
20/200 20/25
þ þ
þ
0.60 (168/282) 0.56 (120/214)
32
Bevacizumab (8) F/U loss
þ
20/63 20/32 20/200
Subsensory Within the concavity
1.125 Sub-RPE
Others
Subsequent development of CNV
CNV in the other eye Subsequent development of CNV
Within the concavity Within the concavity Within the concavity Within the concavity Within the concavity Within the concavity Over the margin
Classic
NA
NA
0.41 (83/203)
19
Ranibizumab (5)
þ
20/200 20/100
Classic
þ
þ
0.29 (62/217)
17
Bevacizumab (3)
20/25
20/20
History of CSC
Classic
NA
NA
0.69 (154/224)
17
Bevacizumab (3)
20/40
20/20
History of CSC
Classic
þ
0.35 (134/383)
14
Ranibizumab (5)
þ
20/32
20/20
Classic
þ
þ
0.46 (148/324)
13
Bevacizumab (2)
20/50
20/32
Classic
þ
þ
0.74 (265/356)
13
Ranibizumab (3)
20/25
20/20
Classic
NA
NA
0.44 (118/259)
7
Bevacizumab (2)
20/32
20/25
Within the concavity 0.875 Sub-RPE Over the margin 4.0 Sub-RPE Within the concavity 4.0 Sub-RPE Within the concavity 9.5 Subsensory Within the concavity
Classic
þ
0.34 (76/221)
8
Bevacizumab (5)
þ
20/80
20/63
Occult Classic
þ þ
þ þ
0.46 (124/272) 0.76 (297/389)
8 7
Bevacizumab (3) Bevacizumab (4)
þ
20/100 20/32 20/40 20/20
Classic
þ
þ
0.85 (353/413)
6
Bevacizumab (3)
20/25
Classic
0.78 (197/250)
3
Bevacizumab (1)
20/100 20/25
1.125 Sub-RPE
Sub-RPE
Subsequent development of CNV
CNV in the other eye
20/25
MARCH 2014
Anti-VEGF ¼ anti–vascular endothelial growth factor; BCVA ¼ best-corrected visual acuity; CNV ¼ choroidal neovascularization; CSC ¼ central serous chorioretinopathy; FA ¼ fluorescein angiography; F/U ¼ follow-up; ICGA ¼ indocyanine green angiography; NA ¼ not available; OCT ¼ optical coherence tomography; RPE ¼ retinal pigment epithelium; SE ¼ spherical equivalent. a Ratio of choroidal thickness at the base of the focal choroidal excavation and unaffected sites near the excavation. b Total number of injections. c Additional injection after initial 1-3 injections.
FIGURE 1. Type 1 choroidal neovascularization (CNV) with classic pattern in a 40-year-old woman (Case 9). The patient presented with decreased visual acuity of 20/50 in the right eye. (Top left) Biomicroscopic examination demonstrated a subfoveal gray-yellowish lesion suspicious for CNV. The white line corresponds to the section examined with spectral-domain optical coherence tomography (SD OCT). (Middle, left and right) Fluorescein angiography revealed classic pattern CNV with intense leakage in the late phase. (Top middle) Indocyanine green angiography (ICGA) in the early phase revealed choroidal venous dilation and focal hypofluorescence, corresponding to the area of focal choroidal excavation. (Top right) A relatively well defined hyperfluorescence was observed in the late phase of ICGA. (Bottom left) SD OCT showed focal excavation involving the outer retinal layers up to the external limiting membrane (ELM). Irregular elevation of the retinal pigment epithelium (RPE) line with a minimal amount of fluid collection was noted in the macula. A hyperreflective lesion was located beneath the RPE line (type 1 CNV), and this was confined within the concavity of the focal choroidal excavation. (Bottom right) After 2 consecutive injections of bevacizumab, the patient’s best-corrected visual acuity recovered to 20/32 and the fluid was completely absorbed. The regression of the hyperreflective lesion was noted, along with the complete restoration of the ELM and inner segment/outer segment line. After the treatment, SD OCT revealed the focal choroidal excavation more clearly as the RPE band followed the contour of the choroidal excavation.
while 2 cases showed type 1 CNV in their contralateral eye. The spherical equivalent of the refractive error ranged from 12.50 diopters (D) to 1.125 D (mean, 3.48 D). At initial presentation, CNV was accompanied by focal choroidal excavation in 13 of 16 patients. CNV had developed in 3 patients at 2, 11, and 21 months of follow-up, and 2 of them showed a nonconforming pattern. Fifteen CNVs involved the subfoveal area and 1 CNV was juxtafoveal (within 200 mm from the center of the fovea). The mean baseline BCVA was 20/46 (range, 20/200-20/25). The focal choroidal excavation lesions were located subfoveally in 14 of 16 eyes (87.5%) and juxtafoveally in 2 eyes VOL. 157, NO. 3
(12.5%). The mean choroidal thickness was 160 mm (range, 54-353 mm) at the base of the excavation and 272 mm (range, 203-413 mm) at the unaffected sites near the excavation. The ratio of the choroidal thicknesses of the 2 sites varied from 0.25-0.85 (mean, 0.53). According to FA, 14 eyes exhibited a classic appearance with profuse leakage through the mid and late phase (Figures 1-4). The other 2 CNVs were purely occult (Figure 5). All 8 patients under 50 years had classic CNV. Six of 8 patients over 50 years old showed a classic pattern, and the other 2 had occult pattern CNV. ICGA revealed abnormal vasculature consistent with CNV, but
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FIGURE 2. Type 2 choroidal neovascularization (CNV) with classic pattern in a 28-year-old man (Case 4). The patient presented with an abrupt reduction in vision in his right eye. (Top left) His best-corrected visual acuity was 20/200 in the right eye and the fundus photograph demonstrated a subfoveal exudative lesion with serous retinal detachment. The white line corresponds to the section examined with spectral-domain optical coherence tomography (SD OCT). (Top right) Fluorescein angiography showed classic CNV. (Bottom left) Indocyanine green angiography revealed focal hypofluorescence at the area of focal choroidal excavation and abnormal vessels representing CNV that extended over the margin of the hypofluorescent area (white arrows). (Bottom right) SD OCT demonstrated focal choroidal excavation in the macula and a distinct layer of hyperreflective material located above the retinal pigment epithelium line (type 2 CNV). The hyperreflective tissue extended over the boundary of focal choroidal excavation, and subretinal and intraretinal fluid accumulation was noted.
no polypoidal lesions. Eleven of 12 eyes (91.7%) showed focal hypofluorescence at the corresponding focal choroidal excavation area, and 8 of 12 eyes (66.7%) showed choroidal venous dilation and diffuse hyperfluorescence in the late phase. In all 16 eyes, a hyperreflective subretinal or sub-RPE lesion, representing a CNV complex, was observed on OCT. The location and extent of the lesion was well correlated with the area of hyperfluorescence on FA or abnormal vessels on ICGA. Type 1 CNV was identified in 9 eyes, and type 2 CNV was found in 7 eyes. Among the 8 patients under 50 years old, 2 and 6 patients had type 1 (Figure 1) and type 2 CNV (Figures 2 and 3), respectively. Seven of 8 patients over 50 years old had type 1 CNV (Figures 4 and 5), and the remaining patient had type 2 CNV. A variable amount of subretinal fluid accumulation was observed in all 16 eyes and intraretinal fluid was noted in 5 eyes. 714
All 7 eyes with type 2 CNV on OCT exhibited a classic pattern on FA. Among the 9 eyes with type 1 CNV, 2 eyes exhibited an occult pattern on FA and 7 eyes showed a classic pattern. Hyperreflective lesions on OCT were confined to the boundary of the focal choroidal excavation in 12 eyes. These eyes had a classic appearance on FA, even in type 1 CNV (Figures 1 and 4). In 2 eyes with type 2 CNV, the hyperreflective lesion extended slightly over the margin of excavation with a corresponding classic pattern on FA (Figures 2 and 3). In 2 eyes with type 1 CNV, highly reflective tissue beneath the RPE extended far away from the excavation, corresponding to an occult pattern with irregular RPE elevation (Figure 5). The mean follow-up period was 14.5 months (range: 3-35 months) and all but 1 patient were treated with anti-VEGF injections. A total of 11 eyes were treated with bevacizumab and 4 eyes were treated with ranibizumab,
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FIGURE 3. Type 2 choroidal neovascularization (CNV) with classic pattern in a 29-year-old woman (Case 11). The patient presented with vague visual disturbance and her best-corrected visual acuity (BCVA) was 20/25 in the right eye. (Top left) Initial spectral-domain optical coherence tomography (SD OCT) scan through the fovea revealed focal choroidal excavation with slight separation between sensory retina and retinal pigment epithelium (RPE). (Top right) Initial fluorescein angiography (FA) showed nonspecific RPE mottling with no leakage. Two months later, her BCVA decreased to 20/32. (Middle left) SD OCT showed subretinal fluid with hyperreflective material located above the RPE line (type 2 CNV). (Bottom right) At that time, FA demonstrated welldefined CNV with progressive leakage. After 2 consecutive injections of bevacizumab, her BCVA recovered to 20/25. (Bottom left) Follow-up SD OCT disclosed regressed CNV.
with a mean of 3.7 injections. The mean BCVA in these eyes improved from 20/44 (range: 20/200-20/25) at baseline to 20/26 (range: 20/100-20/20) at the last visit. Fluid collection in the macular area was not observed in any patient at the last visit. All 7 patients under 50 years old achieved a final BCVA of 20/32 or better with a mean of 2.1 (range: 1-3) injections during the mean follow-up period of 11.7 months (range: 3-19 months). Additional treatment was not required after the 1-3 initial injections (Figures 1 and 3). All 8 patients over 50 years old attained visual improvement with a mean of 5.0 injections (range: 3-8) during the mean follow-up period of 17.0 months (range: 7-35 months), and 6 had a final BCVA better than 20/32. Complete absorption of fluid was observed after 3 initial loading injections in all eyes. Additional treatment of 1-5 injections was given in 6 eyes for recurrent fluid collection (Figure 4).
DISCUSSION IN OUR SERIES, ALL 16 CHOROIDAL NEOVASCULAR COM-
plexes involved the area of choroidal excavation on VOL. 157, NO. 3
OCT, with 12 being located within the boundary of excavation and 4 extending over the margin. This close topographic relationship supports the notion that choroidal excavation plays a role in the development of CNV. Choroidal thinning at the area of excavation was observed in nearly all patients, which is consistent with the results of other studies.4,5 By ICGA, focal hypofluorescence was observed in this area, which indicates choroidal hypoperfusion. The results of numerous studies strongly support the role of choroidal hypoperfusion and possible ischemia as an inciting factor for CNV formation in AMD.13–18 We postulated that mechanical stretching of the RPE/Bruch membrane complex in the area corresponding to choroidal excavation can result in a focal defect in the Bruch membrane through which new vessels can extend from the choroid. Additionally, in vitro, the stretching of the RPE cells has been reported to induce the production and secretion of VEGF.19 Seven of 16 patients in our series had type 2 CNV on SD OCT and 6 of them were under the age of 50. Margolis and associates suggested that the elasticity of the retina would initially allow the photoreceptors to remain attached to the RPE (conforming pattern).4 With time, stress on the
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FIGURE 4. Type 1 choroidal neovascularization (CNV) with classic pattern in a 71-year-old man (Case 2). The patient was referred for evaluation of exudative age-related macular degeneration in his left eye. The best-corrected visual acuity (BCVA) was 20/200 at initial presentation. (Top left) Biomicroscopic examination demonstrated suspicious CNV surrounded by hemorrhage. A few soft drusen were noted in the extramacular area. The white line corresponds to the section examined with spectral-domain optical coherence tomography (SD OCT). (Top second) Fluorescein angiography showed an area of discrete hyperfluorescence in the early phase. (Top third) A well-defined neovascular network was noted in the early phase of indocyanine green angiography. (Top right) Initial SD OCT taken at the previous hospital showed subretinal fluid with a hyperreflective lesion, mostly located beneath the retinal pigment epithelium (RPE) line. After 3 loading injections of ranibizumab, the BCVA improved to 20/25. (Bottom left) A fundus photograph taken 12 months after initial presentation demonstrated the regression of CNV. Atrophic changes of the RPE were noted in the area of the focal choroidal excavation. (Bottom middle) Complete absorption of subretinal fluid and regression of the hyperreflective lesion was observed on follow-up SD OCT. Focal choroidal excavation was more obvious on SD OCT after the regression of the hyperreflective lesion. (Bottom right) Fifteen months after presentation, CNV recurrence was noted with subretinal fluid accumulation on follow-up SD OCT. A hyperreflective lesion was observed again beneath the RPE line. Additional injections with ranibizumab were performed, resulting in complete absorption of fluid again. Final BCVA was 20/25.
outer retina could result in the separation of the photoreceptor tips from the apical surface of the RPE, leading to the formation of a subretinal space (nonconforming pattern). New vessels then can grow into this space without any resistance. Furthermore, the potential metabolic stress and ischemic insult to the outer retina and RPE after longstanding disintegration may also serve as a potential driving force for the ingrowth of neovascularization in a nonconforming pattern. Nonconforming choroidal excavation may have a greater tendency to develop secondary CNV, compared to the conforming pattern. However, this remains speculative because most of the CNV in this study was already present at initial examination. Type 1 CNV was observed in 9 patients, 7 of whom were over the age of 50. The age profile of our patients is compatible with the pathogenesis of CNV proposed by Gass.6 Gass suggested that the growth pattern of neovascular proliferation is determined primarily by preexisting disease, as well as by the patient’s age. Given that most of the older patients in our study did not have soft drusen, a common sign of early AMD, and 2 younger patients demonstrated type 1 lesions, anatomic changes of the overlying retinal layers induced by choroidal excavation may also affect 716
the growth pattern. According to the degree and extent of loosening of the adhesion between the surrounding RPE and Bruch membrane, new vessels extending from the choroid through the focal defects in the Bruch membrane may grow laterally, beneath the RPE layer, or anteriorly, beneath the sensory retina. It is notable that in our series, 7 of 9 patients with type 1 CNV on OCT had a classic pattern with profuse leakage on FA. In these 7 eyes, entire abnormal vascular complexes were located within the concavity of the focal choroidal excavation (Figures 1 and 4). In contrast, in 2 eyes with an occult appearance, the neovascular complexes extended beyond the margin of excavation with irregular RPE elevation on OCT. It is likely that a healthy RPE and the relatively firm adhesion of the RPE and Bruch membrane surrounding the focal choroidal excavation may limit active CNV proliferation within the focal choroidal excavation boundary. We postulated that this characteristic contributed to the well-defined, classic appearance on FA even though the CNV is located beneath the RPE layer. Owing to the small number of cases and different followup periods, our interpretation of the prognosis of this disorder is currently limited. Nonetheless, the visual prognosis
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FIGURE 5. Type 1 choroidal neovascularization (CNV) with occult pattern in a 66-year-old man (Case 13). The patient presented with decreased visual acuity of 20/100 in the right eye. (Left column, top) Fluorescein angiography (FA) showed occult CNV with irregular and diffuse leakage. (Left column, bottom) A well-defined hyperfluorescence, so-called plaque lesion, was observed in the late phase of indocyanine green angiography. Hypofluorescence corresponds to the area of focal choroidal excavation. (Right column) The 3 spectral-domain optical coherence tomography (SD OCT) images were arranged in order from the lowest white line (top) to the highest (bottom) in the FA image (Left column, top). (Right column, top) On SD OCT, hyperreflective materials beneath the retinal pigment epithelium (RPE) line were noted at the base of the focal choroidal excavation. These extended over the margin of the focal choroidal excavation associated with irregular RPE elevation. (Right column, middle and bottom) There was an accumulation of intraretinal fluid and a minimal amount of subretinal fluid. The disruption of the external limiting membrane and inner segment/outer segment line was noted.
with anti-VEGF treatment in our patients was seemingly favorable. Less frequent injection was required even in patients over 50 years compared with typical neovascular AMD.20 Our study has limitations inherent to a small retrospective analysis performed at a single institution. We carefully reviewed the OCT images of all patients who were diagnosed with CNV over the study period, which lasted longer than 4 years, and collected a relatively large number of cases that were uncommon. Despite the close topographic relationship observed, it is possible that focal choroidal excavation was detected coincidentally with CNV, especially in 2 eyes with a large occult pattern. Angiographic classification of CNV can vary between observers. Also, anatomic classification may vary between different models of OCT. However, 14 of 16 CNVs were obvious classiconly pattern. Both OCTs used in this study were SD OCT, which had enough resolution to identify CNV and its location. Finally, the precise determination of CNV type on OCT may be hindered by other pathologic changes, such as exudates or clusters of fibrin and hemorrhage that may also appear as highly reflective lesions. VOL. 157, NO. 3
Nonetheless, the comparison between serial OCT and angiograms showed good co-localization of the neovascular lesions in this study. In summary, taking into consideration all of the imaging and clinical features observed in this study, as well as the results of previous reports, a direct causal relationship between focal choroidal excavation and CNV development seems plausible. Focal choroidal ischemia, overlying RPE changes, and occasional separation of the sensory retina from the RPE layer in focal choroidal excavation may serve as a predisposition for CNV development. It is highly possible that mechanical stretching of the overlying retinal layer may result in a focal break in the Bruch membrane, inducing neovascular proliferation from the choroid. The CNV growth pattern (type 1 or type 2 CNV) may be determined by the anatomic changes in retinal layers associated with focal choroidal excavation, as well as age. Specifically, the growth pattern is dependent on the degree and extent of loosening of the adhesion between the RPE and Bruch membrane. Because the CNV is frequently located within the concavity of the focal choroidal excavation, FA seems to indicate a well-defined classic pattern, even in type 1
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CNV. Smaller lesion size within the focal choroidal excavation cavity, younger age of onset, and a relatively healthy surrounding RPE seem to contribute to notable, favorable
visual outcomes. Further long-term studies with larger patient cohorts are required to elucidate the exact pathophysiology and visual prognosis of this novel disease.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Won Ki Lee has served on advisory boards for Novartis and Bayer, and has received consultancy fees from these companies. He has received payments for lectures from Novartis, Bayer, and Allergan. Jae Hyung Lee has no financial disclosure to report. The authors indicate no funding or financial support. Contributions of authors: design and conduct of the study (W.K.L., J.H.L.); collection and management of data (J.H.L., W.K.L.); analysis and interpretation of the data (W.K.L., J.H.L.); preparation of the manuscript (J.H.L., W.K.L.); review or approval of the manuscript (W.K.L., J.H.L.).
REFERENCES 1. Jampol LM, Shankle J, Schroeder R, Tornambe P, Spaide RF, Hee MR. Diagnostic and therapeutic challenges. Retina 2006; 26(9):1072–1076. 2. Katome T, Mitamura Y, Hotta F, Niki M, Naito T. Two cases of focal choroidal excavation detected by spectral-domain optical coherence tomography. Case Rep Ophthalmol 2012; 3(1):96–103. 3. Wakabayashi Y, Nishimura A, Higashide T, Ijiri S, Sugiyama K. Unilateral choroidal excavation in the macula detected by spectral-domain optical coherence tomography. Acta Ophthalmol 2010;88(3):e87–91. 4. Margolis R, Mukkamala SK, Jampol LM, et al. The expanded spectrum of focal choroidal excavation. Arch Ophthalmol 2011;129(10):1320–1325. 5. Obata R, Takahashi H, Ueta T, Yuda K, Kure K, Yanagi Y. Tomographic and angiographic characteristics of eyes with macular focal choroidal excavation. Retina 2013;33(6): 1201–1210. 6. Gass JDM. Stereoscopic atlas of macular disease: diagnosis and treatment. 4th ed. St Louis: Mosby; 1997:26–37. 7. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina 2008;28(2):201–211. 8. Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the macular photocoagulation study. Macular Photocoagulation Study Group. Arch Ophthalmol 1991;109(9): 1242–1257. 9. Malamos P, Sacu S, Georgopoulos M, Kiss C, Pruente C, Schmidt-Erfurth U. Correlation of high-definition optical coherence tomography and fluorescein angiography imaging in neovascular macular degeneration. Invest Ophthalmol Vis Sci 2009;50(10):4926–4933. 10. Park SS, Truong SN, Zawadzki RJ, et al. High-resolution Fourier-domain optical coherence tomography of choroidal neovascular membranes associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51(8): 4200–4206.
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11. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146(4):496–500. 12. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol 1999;117(10):1329–1345. 13. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118(5):840–845. 14. Metelitsina TI, Grunwald JE, DuPont JC, Ying GS, Brucker AJ, Dunaief JL. Foveolar choroidal circulation and choroidal neovascularization in age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49(1):358–363. 15. Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, de Jong PT. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 1994;35(6):2857–2864. 16. Spaide RF. Age-related choroidal atrophy. Am J Ophthalmol 2009;147(5):801–810. 17. McLeod DS, Grebe R, Bhutto I, Merges C, Baba T, Lutty GA. Relationship between RPE and choriocapillaris in age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50(10): 4982–4991. 18. Hayashi K, de Laey JJ. Indocyanine green angiography of choroidal neovascular membranes. Ophthalmologica 1985; 190(1):30–39. 19. Seko Y, Seko Y, Fujikura H, Pang J, Tokoro T, Shimokawa H. Induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro. Invest Ophthalmol Vis Sci 1999;40(13):3287–3291. 20. Comparison of Age-Related Macular Degeneration Treatments Trials Research Group; Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-relatedmacular degeneration: two-year results. Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology 2012;119(7):1388–1398.
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Biosketch Jae Hyung Lee, MD, graduated from Catholic University of Korea, College of Medicine in 2008 where he completed internship and residency in 2013. He is currently pursuing his first year of retinal fellowship in Seoul St. Mary’s Hospital. His research interests include age-related macular degeneration and polypoidal choroidal vasculopathy.
VOL. 157, NO. 3
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PURPOSE:
To describe the clinical and imaging characteristics of choroidal neovascularization (CNV) accompanied by focal choroidal excavation. DESIGN: Retrospective, interventional case series. METHODS: The medical records of 16 patients (16 eyes) were reviewed. Imaging findings including fluorescein angiography (FA), indocyanine green angiography, and spectral-domain optical coherence tomography (SD OCT) were analyzed. RESULTS: CNV complexes were primarily located beneath the retinal pigment epithelium (type 1 CNV) in 9 eyes and in the subneurosensory retinal space (type 2 CNV) in 7 eyes, as assessed by SD OCT. Seven of 8 patients over 50 years old had type 1 CNV, and 6 of 8 patients under 50 had type 2 lesions. All 7 eyes with type 2 CNV exhibited classic CNV on FA. Additionally, 7 of 9 eyes with type 1 CNV had the classic pattern, and in these eyes, the CNV complexes were confined to the concavity of choroidal excavation. In 15 patients treated by anti–vascular endothelial growth factor (anti-VEGF) injections, the mean best-corrected visual acuity improved from 20/44 to 20/26 with a mean of 3.7 injections during a mean follow-up period of 14.5 months. CONCLUSIONS: The CNV growth pattern and extent seem to be determined by the degree of damage to the retinal pigment epithelium/Bruch membrane complex resulting from choroidal excavation, as well as age. Neovascular complexes tend to be located within the boundary of choroidal excavation and are revealed as classic patterns on FA, even in type 1 CNV. AntiVEGF was notably effective for treating these lesions, with a low rate of recurrence. (Am J Ophthalmol 2014;157:710–718. Ó 2014 by Elsevier Inc. All rights reserved.)
C
HOROIDAL EXCAVATION WAS FIRST REPORTED
as an unusual finding on time-domain optical coherence tomography (OCT) by Jampol and
Accepted for publication Dec 4, 2013. From the Department of Ophthalmology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Inquiries to Won Ki Lee, Department of Ophthalmology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-701, South Korea; e-mail: [email protected]
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2014 BY
associates.1 After a few reports of similar cases detected by spectral-domain optical coherence tomography (SD OCT),2,3 Margolis and associates4 named this entity focal choroidal excavation. In 2 recent reports, most focal choroidal excavation lesions were shown to remain stable over a 1- or 3-year follow-up period.4,5 In a portion of patients, there was a history of central serous chorioretinopathy (CSC) or the concomitant presence of CSC. Cicatrized subretinal neovascularization was also noted at initial presentation in certain patients, while in others, secondary choroidal neovascularization (CNV) developed during the follow-up. The authors suggested a possible association between abnormal choroidal circulation in focal choroidal excavation and pathologic lesions. However, it has not been determined whether CNV develops as a clinical consequence of focal choroidal excavation or if they are 2 unrelated diseases that were coincidentally detected simultaneously. The paucity of cases has made it difficult to make conclusions regarding the role of focal choroidal excavation in CNV development. There are several characteristic features of focal choroidal excavation that indicate that it may provide the appropriate milieu for CNV development. Previous studies showed that focal choroidal thinning and hypoperfusion was associated with focal choroidal excavation. Additionally, varying degrees of pigmentary disturbances and retinal pigment epithelium (RPE) alterations were noted.3–5 It is also possible that the stretching of the RPE/ Bruch membrane in the area of choroidal excavation can result in a focal break in the Bruch membrane, which induces neovascular proliferation from the choroid, as in Gass type 2 CNV. Gass classified the patterns of choroidal neovascular growth into the 2 following pathologic types: type 1, the growth of new vessels beneath the RPE; and type 2, the growth of new vessels in the subsensory retinal space.6 Elderly patients with age-related macular degeneration (AMD), which is associated with diffuse loosening of the firm attachment of the RPE to the Bruch membrane, are prone to developing type 1 CNV. This form of neovascularization is less permeable and proliferates slowly.7,8 Fluorescein angiography (FA) reveals a pattern that is ‘‘poorly defined’’ with minimal leakage, which is also described as occult CNV. In contrast, type 2 CNV occurs primarily in patients younger than 50 years and is associated with focally destructive lesions affecting the
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RPE/Bruch membrane. The firm attachment between the surrounding RPE and Bruch membrane in young individuals was postulated to explain the type 2 growth pattern. Type 2 CNV tends to proliferate rapidly, and FA typically exhibits a ‘‘well-defined’’ pattern with intense leakage, also referred to as classic CNV.7,8 SD OCT enables us to observe the details of retinal structures and the level of retinal involvement in CNV. Studies using SD OCT demonstrated a relatively good correlation between the angiographic classification (occult vs classic) and the anatomic classification of CNV (type 1 vs type 2).9,10 The purpose of this study was to evaluate the detailed clinical and imaging characteristics in patients with CNV accompanied by focal choroidal excavation, focusing particularly on the association between the angiographic pattern and the anatomic pattern on OCT. We also suggest a hypothetical angiogenic process in this newly described disease entity.
METHODS WE ANALYZED THE MEDICAL RECORDS AND IMAGING
studies of 689 eyes from 653 consecutive patients with CNV or polypoidal choroidal vasculopathy who were referred to the ophthalmology department of Seoul St. Mary’s Hospital, The Catholic University of Korea, between the beginning of January 2009 and the end of March 2013. Sixteen patients were diagnosed as having CNV accompanied by focal choroidal excavation. Detailed clinical and imaging characteristics were evaluated in these patients. This retrospective study was approved by the Institutional Review Board of the Catholic Medical Center and conducted in accordance with the tenets of the Declaration of Helsinki. All patients received a complete ocular examination, including best-corrected visual acuity (BCVA) measurement using a Snellen visual acuity chart, slit-lamp biomicroscopy with a noncontact or contact lens, and OCT at baseline and at each follow-up visit. Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) was used for SD OCT examinations after November 2011. The raster scan of Spectralis OCT was performed on each eye centered at the fovea using 2 scan protocols: a conventional protocol and an enhanced depth imaging (EDI) protocol.11 Before that time, Cirrus OCT (Carl Zeiss Meditec, Dublin, California, USA) with macular cube program consisting of 128 horizontal lines of 512 A-scans was used. All 16 patients underwent EDI OCT using Spectralis OCT at least once during their follow-up. FA and indocyanine green angiography (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany) were performed at baseline and on a patient-by-patient basis thereafter. However, indocyanine green angiography (ICGA) was not VOL. 157, NO. 3
performed in 4 eyes at baseline. The Topcon IMAGEnet Digital Imaging System (Topcon, Tokyo, Japan) was used for FA examination in some patients. The diagnosis of focal choroidal excavation was based on SD OCT findings of local excavation of the RPE and Bruch membrane line. Staphylomatous excavation of the sclerochoroidal junction was ruled out with EDI OCT. EDI OCT was used to determine choroidal thickness at the base of the focal choroidal excavation and the unaffected sites near the excavation by measuring the distance from the outer portion of the hyperreflective RPE line to the inner surface of the sclera with the digital calipers included in the review software. The ratio of the choroidal thicknesses of the 2 sites was calculated. The diagnosis and classification of CNV were based on the FA and SD OCT findings. According to FA, CNVs were labeled classic or occult based on the Treatment of AgeRelated Macular Degeneration With Photodynamic Therapy (TAP) protocol.12 The anatomic classification of CNV was made based on the location of the CNV membrane appearing as a highly reflective lesion on SD OCT with respect to the RPE band. CNV was classified as type 1 when the highly reflective lesion was primarily identified in the sub-RPE space and as type 2 when it was predominantly localized in the subretinal space. The topographic association between choroidal excavation and the hyperreflective lesion was also evaluated. The ICGA images were analyzed to identify aberrant vessels or polypoidal lesions and any abnormal hypofluorescent or hyperfluoresecnt areas. All patients were treated with intravitreal anti–vascular endothelial growth factor (anti-VEGF) injection with either bevacizumab (Avastin; Genentech, Inc, San Francisco, California, USA) or ranibizumab (Lucentis; Genentech Inc), except for 1 patient who was lost to follow-up. Anti-VEGF treatment was performed on an as-needed basis, after either an initial 2 or 3 consecutive injections or a single injection. Repeated injections were given whenever either intraretinal or subretinal fluid involving the fovea was detected on follow-up OCT. The patients were followed up regularly at 1- to 6-month intervals, depending on lesion activity, but the intervals did not exceed 3 months in patients over 50 years old.
RESULTS THE PATIENT CHARACTERISTICS ARE SUMMARIZED IN THE
Table. We studied 16 eyes in 16 Korean patients, 9 of whom were women. The mean age was 49.6 years (range, 28-86 years). Eight patients were under 50 years old; 2 among them had a history of CSC in the affected eyes and 1 patient had high myopia. Soft drusen was only noted in 1 of 8 patients over 50. None of the patients had a history of medical illness, medication use, or a family history of retinal disease. None of the cases were bilaterally affected,
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TABLE. Clinical Characteristics of Patients With Choroidal Neovascularization Associated With Focal Choroidal Excavation OCT
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Case No.
Age/Sex
1
39/M
Left
2
71/M
Left
3 4
86/F 28/M
Left Right
5
69/F
Left
6
45/M
Right
2.125 Subsensory
7
47/F
Left
6.5
Subsensory
8
55/M
Right
0.5
Sub-RPE
9
40/F
Right
2.75
Sub RPE
10
53/F
Right
3.125 Subsensory
11
29/F
Right
7.125 Subsensory
12
53/M
Left
0.5
13 14
66/M 54/F
Right Right
15
28/F
Left
16
30/F
Right
Eye
SE
12.5
CNV Pattern
Extent of CNV
FA CNV Pattern
ICGA
BCVA
Ratio of Choroidal F/U Focal Late Thicknessa (Months) Hypofluoresence Hyperfluoresence
Anti-VEGF (Nb)
Additional Injectionc
Initial
Final
20/25
Classic
NA
NA
0.50 (114/228)
19
Bevacizumab (1)
20/32
Within the Classic concavity 0.625 Sub-RPE Over the margin Occult 4.5 Subsensory Over the margin Classic
þ
þ
0.25 (54/216)
35
Ranibizumab (7)
þ
20/200 20/25
þ þ
þ
0.60 (168/282) 0.56 (120/214)
32
Bevacizumab (8) F/U loss
þ
20/63 20/32 20/200
Subsensory Within the concavity
1.125 Sub-RPE
Others
Subsequent development of CNV
CNV in the other eye Subsequent development of CNV
Within the concavity Within the concavity Within the concavity Within the concavity Within the concavity Within the concavity Over the margin
Classic
NA
NA
0.41 (83/203)
19
Ranibizumab (5)
þ
20/200 20/100
Classic
þ
þ
0.29 (62/217)
17
Bevacizumab (3)
20/25
20/20
History of CSC
Classic
NA
NA
0.69 (154/224)
17
Bevacizumab (3)
20/40
20/20
History of CSC
Classic
þ
0.35 (134/383)
14
Ranibizumab (5)
þ
20/32
20/20
Classic
þ
þ
0.46 (148/324)
13
Bevacizumab (2)
20/50
20/32
Classic
þ
þ
0.74 (265/356)
13
Ranibizumab (3)
20/25
20/20
Classic
NA
NA
0.44 (118/259)
7
Bevacizumab (2)
20/32
20/25
Within the concavity 0.875 Sub-RPE Over the margin 4.0 Sub-RPE Within the concavity 4.0 Sub-RPE Within the concavity 9.5 Subsensory Within the concavity
Classic
þ
0.34 (76/221)
8
Bevacizumab (5)
þ
20/80
20/63
Occult Classic
þ þ
þ þ
0.46 (124/272) 0.76 (297/389)
8 7
Bevacizumab (3) Bevacizumab (4)
þ
20/100 20/32 20/40 20/20
Classic
þ
þ
0.85 (353/413)
6
Bevacizumab (3)
20/25
Classic
0.78 (197/250)
3
Bevacizumab (1)
20/100 20/25
1.125 Sub-RPE
Sub-RPE
Subsequent development of CNV
CNV in the other eye
20/25
MARCH 2014
Anti-VEGF ¼ anti–vascular endothelial growth factor; BCVA ¼ best-corrected visual acuity; CNV ¼ choroidal neovascularization; CSC ¼ central serous chorioretinopathy; FA ¼ fluorescein angiography; F/U ¼ follow-up; ICGA ¼ indocyanine green angiography; NA ¼ not available; OCT ¼ optical coherence tomography; RPE ¼ retinal pigment epithelium; SE ¼ spherical equivalent. a Ratio of choroidal thickness at the base of the focal choroidal excavation and unaffected sites near the excavation. b Total number of injections. c Additional injection after initial 1-3 injections.
FIGURE 1. Type 1 choroidal neovascularization (CNV) with classic pattern in a 40-year-old woman (Case 9). The patient presented with decreased visual acuity of 20/50 in the right eye. (Top left) Biomicroscopic examination demonstrated a subfoveal gray-yellowish lesion suspicious for CNV. The white line corresponds to the section examined with spectral-domain optical coherence tomography (SD OCT). (Middle, left and right) Fluorescein angiography revealed classic pattern CNV with intense leakage in the late phase. (Top middle) Indocyanine green angiography (ICGA) in the early phase revealed choroidal venous dilation and focal hypofluorescence, corresponding to the area of focal choroidal excavation. (Top right) A relatively well defined hyperfluorescence was observed in the late phase of ICGA. (Bottom left) SD OCT showed focal excavation involving the outer retinal layers up to the external limiting membrane (ELM). Irregular elevation of the retinal pigment epithelium (RPE) line with a minimal amount of fluid collection was noted in the macula. A hyperreflective lesion was located beneath the RPE line (type 1 CNV), and this was confined within the concavity of the focal choroidal excavation. (Bottom right) After 2 consecutive injections of bevacizumab, the patient’s best-corrected visual acuity recovered to 20/32 and the fluid was completely absorbed. The regression of the hyperreflective lesion was noted, along with the complete restoration of the ELM and inner segment/outer segment line. After the treatment, SD OCT revealed the focal choroidal excavation more clearly as the RPE band followed the contour of the choroidal excavation.
while 2 cases showed type 1 CNV in their contralateral eye. The spherical equivalent of the refractive error ranged from 12.50 diopters (D) to 1.125 D (mean, 3.48 D). At initial presentation, CNV was accompanied by focal choroidal excavation in 13 of 16 patients. CNV had developed in 3 patients at 2, 11, and 21 months of follow-up, and 2 of them showed a nonconforming pattern. Fifteen CNVs involved the subfoveal area and 1 CNV was juxtafoveal (within 200 mm from the center of the fovea). The mean baseline BCVA was 20/46 (range, 20/200-20/25). The focal choroidal excavation lesions were located subfoveally in 14 of 16 eyes (87.5%) and juxtafoveally in 2 eyes VOL. 157, NO. 3
(12.5%). The mean choroidal thickness was 160 mm (range, 54-353 mm) at the base of the excavation and 272 mm (range, 203-413 mm) at the unaffected sites near the excavation. The ratio of the choroidal thicknesses of the 2 sites varied from 0.25-0.85 (mean, 0.53). According to FA, 14 eyes exhibited a classic appearance with profuse leakage through the mid and late phase (Figures 1-4). The other 2 CNVs were purely occult (Figure 5). All 8 patients under 50 years had classic CNV. Six of 8 patients over 50 years old showed a classic pattern, and the other 2 had occult pattern CNV. ICGA revealed abnormal vasculature consistent with CNV, but
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FIGURE 2. Type 2 choroidal neovascularization (CNV) with classic pattern in a 28-year-old man (Case 4). The patient presented with an abrupt reduction in vision in his right eye. (Top left) His best-corrected visual acuity was 20/200 in the right eye and the fundus photograph demonstrated a subfoveal exudative lesion with serous retinal detachment. The white line corresponds to the section examined with spectral-domain optical coherence tomography (SD OCT). (Top right) Fluorescein angiography showed classic CNV. (Bottom left) Indocyanine green angiography revealed focal hypofluorescence at the area of focal choroidal excavation and abnormal vessels representing CNV that extended over the margin of the hypofluorescent area (white arrows). (Bottom right) SD OCT demonstrated focal choroidal excavation in the macula and a distinct layer of hyperreflective material located above the retinal pigment epithelium line (type 2 CNV). The hyperreflective tissue extended over the boundary of focal choroidal excavation, and subretinal and intraretinal fluid accumulation was noted.
no polypoidal lesions. Eleven of 12 eyes (91.7%) showed focal hypofluorescence at the corresponding focal choroidal excavation area, and 8 of 12 eyes (66.7%) showed choroidal venous dilation and diffuse hyperfluorescence in the late phase. In all 16 eyes, a hyperreflective subretinal or sub-RPE lesion, representing a CNV complex, was observed on OCT. The location and extent of the lesion was well correlated with the area of hyperfluorescence on FA or abnormal vessels on ICGA. Type 1 CNV was identified in 9 eyes, and type 2 CNV was found in 7 eyes. Among the 8 patients under 50 years old, 2 and 6 patients had type 1 (Figure 1) and type 2 CNV (Figures 2 and 3), respectively. Seven of 8 patients over 50 years old had type 1 CNV (Figures 4 and 5), and the remaining patient had type 2 CNV. A variable amount of subretinal fluid accumulation was observed in all 16 eyes and intraretinal fluid was noted in 5 eyes. 714
All 7 eyes with type 2 CNV on OCT exhibited a classic pattern on FA. Among the 9 eyes with type 1 CNV, 2 eyes exhibited an occult pattern on FA and 7 eyes showed a classic pattern. Hyperreflective lesions on OCT were confined to the boundary of the focal choroidal excavation in 12 eyes. These eyes had a classic appearance on FA, even in type 1 CNV (Figures 1 and 4). In 2 eyes with type 2 CNV, the hyperreflective lesion extended slightly over the margin of excavation with a corresponding classic pattern on FA (Figures 2 and 3). In 2 eyes with type 1 CNV, highly reflective tissue beneath the RPE extended far away from the excavation, corresponding to an occult pattern with irregular RPE elevation (Figure 5). The mean follow-up period was 14.5 months (range: 3-35 months) and all but 1 patient were treated with anti-VEGF injections. A total of 11 eyes were treated with bevacizumab and 4 eyes were treated with ranibizumab,
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FIGURE 3. Type 2 choroidal neovascularization (CNV) with classic pattern in a 29-year-old woman (Case 11). The patient presented with vague visual disturbance and her best-corrected visual acuity (BCVA) was 20/25 in the right eye. (Top left) Initial spectral-domain optical coherence tomography (SD OCT) scan through the fovea revealed focal choroidal excavation with slight separation between sensory retina and retinal pigment epithelium (RPE). (Top right) Initial fluorescein angiography (FA) showed nonspecific RPE mottling with no leakage. Two months later, her BCVA decreased to 20/32. (Middle left) SD OCT showed subretinal fluid with hyperreflective material located above the RPE line (type 2 CNV). (Bottom right) At that time, FA demonstrated welldefined CNV with progressive leakage. After 2 consecutive injections of bevacizumab, her BCVA recovered to 20/25. (Bottom left) Follow-up SD OCT disclosed regressed CNV.
with a mean of 3.7 injections. The mean BCVA in these eyes improved from 20/44 (range: 20/200-20/25) at baseline to 20/26 (range: 20/100-20/20) at the last visit. Fluid collection in the macular area was not observed in any patient at the last visit. All 7 patients under 50 years old achieved a final BCVA of 20/32 or better with a mean of 2.1 (range: 1-3) injections during the mean follow-up period of 11.7 months (range: 3-19 months). Additional treatment was not required after the 1-3 initial injections (Figures 1 and 3). All 8 patients over 50 years old attained visual improvement with a mean of 5.0 injections (range: 3-8) during the mean follow-up period of 17.0 months (range: 7-35 months), and 6 had a final BCVA better than 20/32. Complete absorption of fluid was observed after 3 initial loading injections in all eyes. Additional treatment of 1-5 injections was given in 6 eyes for recurrent fluid collection (Figure 4).
DISCUSSION IN OUR SERIES, ALL 16 CHOROIDAL NEOVASCULAR COM-
plexes involved the area of choroidal excavation on VOL. 157, NO. 3
OCT, with 12 being located within the boundary of excavation and 4 extending over the margin. This close topographic relationship supports the notion that choroidal excavation plays a role in the development of CNV. Choroidal thinning at the area of excavation was observed in nearly all patients, which is consistent with the results of other studies.4,5 By ICGA, focal hypofluorescence was observed in this area, which indicates choroidal hypoperfusion. The results of numerous studies strongly support the role of choroidal hypoperfusion and possible ischemia as an inciting factor for CNV formation in AMD.13–18 We postulated that mechanical stretching of the RPE/Bruch membrane complex in the area corresponding to choroidal excavation can result in a focal defect in the Bruch membrane through which new vessels can extend from the choroid. Additionally, in vitro, the stretching of the RPE cells has been reported to induce the production and secretion of VEGF.19 Seven of 16 patients in our series had type 2 CNV on SD OCT and 6 of them were under the age of 50. Margolis and associates suggested that the elasticity of the retina would initially allow the photoreceptors to remain attached to the RPE (conforming pattern).4 With time, stress on the
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FIGURE 4. Type 1 choroidal neovascularization (CNV) with classic pattern in a 71-year-old man (Case 2). The patient was referred for evaluation of exudative age-related macular degeneration in his left eye. The best-corrected visual acuity (BCVA) was 20/200 at initial presentation. (Top left) Biomicroscopic examination demonstrated suspicious CNV surrounded by hemorrhage. A few soft drusen were noted in the extramacular area. The white line corresponds to the section examined with spectral-domain optical coherence tomography (SD OCT). (Top second) Fluorescein angiography showed an area of discrete hyperfluorescence in the early phase. (Top third) A well-defined neovascular network was noted in the early phase of indocyanine green angiography. (Top right) Initial SD OCT taken at the previous hospital showed subretinal fluid with a hyperreflective lesion, mostly located beneath the retinal pigment epithelium (RPE) line. After 3 loading injections of ranibizumab, the BCVA improved to 20/25. (Bottom left) A fundus photograph taken 12 months after initial presentation demonstrated the regression of CNV. Atrophic changes of the RPE were noted in the area of the focal choroidal excavation. (Bottom middle) Complete absorption of subretinal fluid and regression of the hyperreflective lesion was observed on follow-up SD OCT. Focal choroidal excavation was more obvious on SD OCT after the regression of the hyperreflective lesion. (Bottom right) Fifteen months after presentation, CNV recurrence was noted with subretinal fluid accumulation on follow-up SD OCT. A hyperreflective lesion was observed again beneath the RPE line. Additional injections with ranibizumab were performed, resulting in complete absorption of fluid again. Final BCVA was 20/25.
outer retina could result in the separation of the photoreceptor tips from the apical surface of the RPE, leading to the formation of a subretinal space (nonconforming pattern). New vessels then can grow into this space without any resistance. Furthermore, the potential metabolic stress and ischemic insult to the outer retina and RPE after longstanding disintegration may also serve as a potential driving force for the ingrowth of neovascularization in a nonconforming pattern. Nonconforming choroidal excavation may have a greater tendency to develop secondary CNV, compared to the conforming pattern. However, this remains speculative because most of the CNV in this study was already present at initial examination. Type 1 CNV was observed in 9 patients, 7 of whom were over the age of 50. The age profile of our patients is compatible with the pathogenesis of CNV proposed by Gass.6 Gass suggested that the growth pattern of neovascular proliferation is determined primarily by preexisting disease, as well as by the patient’s age. Given that most of the older patients in our study did not have soft drusen, a common sign of early AMD, and 2 younger patients demonstrated type 1 lesions, anatomic changes of the overlying retinal layers induced by choroidal excavation may also affect 716
the growth pattern. According to the degree and extent of loosening of the adhesion between the surrounding RPE and Bruch membrane, new vessels extending from the choroid through the focal defects in the Bruch membrane may grow laterally, beneath the RPE layer, or anteriorly, beneath the sensory retina. It is notable that in our series, 7 of 9 patients with type 1 CNV on OCT had a classic pattern with profuse leakage on FA. In these 7 eyes, entire abnormal vascular complexes were located within the concavity of the focal choroidal excavation (Figures 1 and 4). In contrast, in 2 eyes with an occult appearance, the neovascular complexes extended beyond the margin of excavation with irregular RPE elevation on OCT. It is likely that a healthy RPE and the relatively firm adhesion of the RPE and Bruch membrane surrounding the focal choroidal excavation may limit active CNV proliferation within the focal choroidal excavation boundary. We postulated that this characteristic contributed to the well-defined, classic appearance on FA even though the CNV is located beneath the RPE layer. Owing to the small number of cases and different followup periods, our interpretation of the prognosis of this disorder is currently limited. Nonetheless, the visual prognosis
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FIGURE 5. Type 1 choroidal neovascularization (CNV) with occult pattern in a 66-year-old man (Case 13). The patient presented with decreased visual acuity of 20/100 in the right eye. (Left column, top) Fluorescein angiography (FA) showed occult CNV with irregular and diffuse leakage. (Left column, bottom) A well-defined hyperfluorescence, so-called plaque lesion, was observed in the late phase of indocyanine green angiography. Hypofluorescence corresponds to the area of focal choroidal excavation. (Right column) The 3 spectral-domain optical coherence tomography (SD OCT) images were arranged in order from the lowest white line (top) to the highest (bottom) in the FA image (Left column, top). (Right column, top) On SD OCT, hyperreflective materials beneath the retinal pigment epithelium (RPE) line were noted at the base of the focal choroidal excavation. These extended over the margin of the focal choroidal excavation associated with irregular RPE elevation. (Right column, middle and bottom) There was an accumulation of intraretinal fluid and a minimal amount of subretinal fluid. The disruption of the external limiting membrane and inner segment/outer segment line was noted.
with anti-VEGF treatment in our patients was seemingly favorable. Less frequent injection was required even in patients over 50 years compared with typical neovascular AMD.20 Our study has limitations inherent to a small retrospective analysis performed at a single institution. We carefully reviewed the OCT images of all patients who were diagnosed with CNV over the study period, which lasted longer than 4 years, and collected a relatively large number of cases that were uncommon. Despite the close topographic relationship observed, it is possible that focal choroidal excavation was detected coincidentally with CNV, especially in 2 eyes with a large occult pattern. Angiographic classification of CNV can vary between observers. Also, anatomic classification may vary between different models of OCT. However, 14 of 16 CNVs were obvious classiconly pattern. Both OCTs used in this study were SD OCT, which had enough resolution to identify CNV and its location. Finally, the precise determination of CNV type on OCT may be hindered by other pathologic changes, such as exudates or clusters of fibrin and hemorrhage that may also appear as highly reflective lesions. VOL. 157, NO. 3
Nonetheless, the comparison between serial OCT and angiograms showed good co-localization of the neovascular lesions in this study. In summary, taking into consideration all of the imaging and clinical features observed in this study, as well as the results of previous reports, a direct causal relationship between focal choroidal excavation and CNV development seems plausible. Focal choroidal ischemia, overlying RPE changes, and occasional separation of the sensory retina from the RPE layer in focal choroidal excavation may serve as a predisposition for CNV development. It is highly possible that mechanical stretching of the overlying retinal layer may result in a focal break in the Bruch membrane, inducing neovascular proliferation from the choroid. The CNV growth pattern (type 1 or type 2 CNV) may be determined by the anatomic changes in retinal layers associated with focal choroidal excavation, as well as age. Specifically, the growth pattern is dependent on the degree and extent of loosening of the adhesion between the RPE and Bruch membrane. Because the CNV is frequently located within the concavity of the focal choroidal excavation, FA seems to indicate a well-defined classic pattern, even in type 1
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CNV. Smaller lesion size within the focal choroidal excavation cavity, younger age of onset, and a relatively healthy surrounding RPE seem to contribute to notable, favorable
visual outcomes. Further long-term studies with larger patient cohorts are required to elucidate the exact pathophysiology and visual prognosis of this novel disease.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Won Ki Lee has served on advisory boards for Novartis and Bayer, and has received consultancy fees from these companies. He has received payments for lectures from Novartis, Bayer, and Allergan. Jae Hyung Lee has no financial disclosure to report. The authors indicate no funding or financial support. Contributions of authors: design and conduct of the study (W.K.L., J.H.L.); collection and management of data (J.H.L., W.K.L.); analysis and interpretation of the data (W.K.L., J.H.L.); preparation of the manuscript (J.H.L., W.K.L.); review or approval of the manuscript (W.K.L., J.H.L.).
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Biosketch Jae Hyung Lee, MD, graduated from Catholic University of Korea, College of Medicine in 2008 where he completed internship and residency in 2013. He is currently pursuing his first year of retinal fellowship in Seoul St. Mary’s Hospital. His research interests include age-related macular degeneration and polypoidal choroidal vasculopathy.
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